Hypertension reducing composition

ABSTRACT

A composition effective to relax smooth muscles in an individual in an altered state is described. The composition includes a dosage of GABA or GABA-a analogue, and a dosage of at least one of an ACE inhibitor and an ARB combined with the dosage of GABA or GABA-a analogue into a deliverable form.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 61/812,415, filed 16 Apr. 2013.

FIELD OF THE INVENTION

This invention relates to hypertension medications. More particularly,the present invention relates to substances which relax smooth muscletissue.

BACKGROUND OF THE INVENTION

Hypertension in humans is a condition wherein the blood pressure iselevated. This can be due to various causes, such as constriction of theblood vessels. Angiotensin II is a potent vasoconstrictor in the humanbody. It is part of the Renin-Angiotensin system and is activated toincrease blood pressure via constriction of the vessels. Angiotensin IIis formed from angiotensin I in the blood by an angiotensin convertingenzyme (ACE). ACE inhibitors are substances that slow (inhibit) theactivity of the enzyme, which decreases the production of angiotensinII. As a result, the blood vessels are less constricted and bloodpressure is reduced.

Another substance used for reducing blood pressure is Angiotensinreceptor blockers (ARBs). Angiotensin II receptor blockers (ARBs) aresubstances that block the action of angiotensin II by preventingangiotensin II from binding to angiotensin II receptors on bloodvessels. As a result, the blood vessels are less constricted and bloodpressure is reduced.

Preventing the formation of angiotensin II by an angiotensin convertingenzyme inhibitor or blocking the action of angiotensin II on the AT1constricting receptor has been well documented and patented in variousdoses and drugs, namely Angiotensin Converting Enzyme Inhibitors (ACEinhibitors) and Angiotensin Receptor Blockers (ARBs). While thesesubstances have been shown to work, they also have side effects whichare not desirable, and would be better if used in smaller doses.However, reducing the dosage also reduces the effectiveness of thesubstance. It would be highly advantageous, therefore, to remedy theforegoing and other deficiencies inherent in the prior art.

An object of the present invention is to provide a composition whichsynergistically relaxes smooth muscle. Another object of the presentinvention is to provide a composition increasing the effectiveness ofAngiotensin Converting Enzyme Inhibitors (ACE inhibitors) andAngiotensin Receptor Blockers (ARBs).

SUMMARY OF THE INVENTION

Briefly, to achieve the desired objects and advantages of the instantinvention provided is a composition effective to relax smooth muscles inan individual in an altered state. The composition includes a dosage ofGABA or GABA-a analogue, and a dosage of at least one of an ACEinhibitor and a ARB combined with the dosage of GABA or GABA-a analogueinto a deliverable form.

In cooperation with at least one of an ACE-I having a relative dosageeffective to reduce blood pressure a determined amount and an ARB havinga relative dosage effective to reduce blood pressure a determinedamount, a composition is provided. The composition includes a dosage ofGABA or GABA-a analogue and a dosage of at least one of an ACE inhibitorand an ARB, combined with the dosage of GABA or GABA-a analogue into adeliverable form. In the presence of GABA or GABA-a analogue the dosageof at least one of the ACE inhibitor is smaller than the relative dosageto supply the dosage effective to reduce blood pressure by thedetermined amount and the ARB is smaller than the relative dosage tosupply the dosage effective to reduce blood pressure the determinedamount.

Also provided is a method of relaxing smooth muscles in an individualhaving GABA receptors expressed in the individual's smooth muscles andendothelium. The method includes the steps of providing a composition ofa dosage of GABA or GABA-a analogue and a dosage of at least one of anACE inhibitor and a ARB combined into a deliverable form. Thecomposition is delivered to an individual's circulatory system. Thelevel of angiotensin II in the individual is reduced through the actionof the dosage of at least one of the ACE inhibitor and/or the ARB duringa period of time. The GABA receptors are activated through the action ofthe GABA or GABA-a analog during the period of time to promoteproduction and release of smooth muscle relaxing substances by theactivation of the GABA-a receptors.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The present invention is a combination of an existing class ofanti-hypertensive drugs, Angiotensin Converting Enzyme Inhibitors(ACE-I) and/or Angiotensin Receptor Blockers (ARBs), with the amino acidGABA or GABA-a analog, to improve the smooth muscle relaxation response,improved vasodilation and improved blood pressure reducing response, orreducing the dose of current ACE inhibitor and/or ARBs with GABA orGABA-a analogue and achieve the same response. GABA-a analogue is beingused as a term to define a compound that has a potential to bind to aGABA-a receptor and stimulate a response. An example of a GABA-a agonistis Muscimol and the like. Thus, the intent is to create a new class ofdrugs composed of compounds from either ACE-I or ARBs or combinationthereof, with an effective dose of GABA or GABA-a agonist/analogue tostimulate the release of vasodilator compounds such as prostaglandin I₂also referred to as prostacyclin (PGI2) to reduce blood pressure orother effects from the relaxation of smooth muscles. This provides animprovement in blood pressure with a lesser amount of ACE-I, ARBs, orcombinations thereof, thus having less side effects and/or toxicity.Conversely, the composition will enhance the effectiveness of theexisting ACE-I and ARBs

Angiotensin-converting enzyme (ACE) inhibitors block the angiotensinconverting enzyme which is needed to form a substance that narrows bloodvessels. As a result, blood vessels relax and widen (dilate), making iteasier for blood to flow through the vessels, which reduces bloodpressure. These medicines also increase the release of water and sodiumto the urine, which also lowers blood pressure.

Angiotensin II receptor, type 1 or AT₁ receptor is an angiotensinreceptor and mediates the cardiovascular effects of angiotensin II, forour purposes vasoconstriction effects, and is an important effectorcontrolling blood pressure and volume in the cardiovascular system. ARBsare Angiotensin II, type 1 (AT₁) receptor antagonists. That is, theyblock the activation of angiotensin II AT₁ receptors. Blockage of AT₁receptors prevents vasoconstriction, reduces secretion of vasopressin,and reduces production and secretion of aldosterone, amongst otheractions. The combined effect reduces blood pressure.

During experimentation between uterine vessels and systemic vesselsduring pregnancy (altered state), an inverse response between uterineand systemic vessels and their ability to secrete prostacyclin (PGI2), ashort acting smooth muscle relaxer, has been found. Systemic vesselsexposed to GABA, in the presence of Angiotensin Converting Enzymeinhibitors (ACE inhibitor) will prevent vasoconstriction due to anincreased PGI2. Uterine vessels require GABA and angiotensin II toincrease PGI2 and dilate. This mechanism appears to be feto-protectivein cases of hemorrhage and low blood volume. During these timesangiotensin II will increase, dilating the uterine circuit andconstricting the systemic circuit, thereby allowing the maternal bloodto pass by the baby, prolonging the baby's chances of survival. It isbelieved that this mechanism is present in every human but disappearsshortly after birth, then reappears in later adult alteredcardiovascular states. Altered cardiovascular states include essentialhypertension, pregnancy, pulmonary hypertension, Alzheimer's disease,inflammatory bowel disease, anesthesia, and the like. Thus, thecomposition of the present invention is useful for relaxing smoothmuscle and improving blood flow when in the altered state.

The inventor has found that the blood vessels, smooth muscle andendothelium of an individual express GABA-a receptors during an “alteredstate” of the individual. The term altered state is intended to mean astate in which the person is outside the norm, having conditions such asessential hypertension, pulmonary hypertension, malignant hypertension,inflammation, metabolic dysfunction, pregnancy, preeclampsia, undergeneral anesthesia, infection and/or sepsis, auto-immune diseases, renalfailure, and the like. GABA-a receptors release and/or producevasodilatory substances and smooth muscle relaxers in the presence ofGABA or GABA-a analogs, but only in the presence of AII inhibition orblockade. The presence of angiotensin II inhibits the functioning ofthese expressed GABA-a receptors, preventing the release of thesesubstances. In other words, the angiotensin II acts to suppress theaction of the GABA-a receptors. By administering ACE inhibitors or ARBs,the angiotensin II present in the system is reduced, and in the presenceof GABA or GABA-a analog to bind to the GABA-a receptors, results in therelease and/or production of the vasodilator substances and smoothmuscle relaxers. GABA or GABA-a analog binding to the GABA-a receptorsinduces release and/or production, for example, of PGI₂. GABA alone andACE inhibitors or ARBs alone do not have the same effect, as the GABA isineffective with GABA-a receptors inhibited, and ACE inhibitors and ARBsdo not stimulate the GABA-a receptors in the production/release of PGI₂.Together, a synergistic effect occurs which greatly increases theeffectiveness of each of the substances used, over what would occur whenused singly. Thus, a dosage of ACE inhibitor and/or ARB which reducesblood pressure a determined amount, can be reduced to a smaller dosagewith the addition of GABA or GABA-a analog.

The preferred composition can be administered in various dosages, suchas GABA doses of 1 mg/day to 10 gms/day and in various ACE-I doses of 1mg/day to 450 mgs/day, or in various ARB doses of 1 mg/day to 1000mg/day. Dosage can also include any combination of GABA doses 1 mg/dayto 10 gms/day and combination of ACE-I and ARBs. The new drug will beoral or IV, and dosed once, twice or thrice daily.

Ace inhibitors and ARBs tend to have a relatively long half-life in anindividual's system. GABA has a relatively short half-life. In apreferred embodiment, the composition is provided in a time releaseform, with the GABA being released over a longer period of time. Forexample, a tablet can be provided which includes a dosage of ACEinhibitor and/or ARBs in an outer layer, and inner layers of GABA whichrelease over a period of time. In this manner, the ACE inhibitor and/orARBs are delivered into the system and remain there for a period oftime. The GABA, having a shorter time in an individual's system, isreleased over that period of time to provide a constant source of GABAto interact with the ACE inhibitor and/or ARBs. It will be understood byone skilled in the art that various mechanisms for releasing GABA over aperiod of time that ACE inhibitors and ARBs are present in the systemcan be employed, such as capsules, tablets and the like.

While the present invention has been described primarily in terms ofreducing blood pressure, it will be understood that since the GABA-areceptors were found to be present in substantially any smooth muscleand endothelium, the composition of the present invention can be used toeffect any of the various vascular circuits such as pulmonary, coronary,cutaneous, splanchnic and the like. In effect, the composition of thepresent invention can be used to relax any smooth muscle to achievevarious effects such as increasing blood flow in the skin, relieveinflammatory bowel disease and the like. Likewise, since the mainpurpose of the composition is to improve blood flow through bloodvessels, many issues are potentially resolved using this composition.

Various changes and modifications to the embodiments herein chosen forpurposes of illustration will readily occur to those skilled in the art.To the extent that such modifications and variations do not depart fromthe spirit of the invention, they are intended to be included within thescope thereof, which is assessed only by a fair interpretation of thefollowing claims.

Having fully described the invention in such clear and concise terms asto enable those skilled in the art to understand and practice the same,the invention claimed is: 1-10. (canceled)
 11. A method of relaxingsmooth muscles in an individual having GABA receptors expressed in theindividual's smooth muscles and endothelium, the method comprising thesteps of: providing a composition of a dosage of GABA or GABA-a analogueand a dosage of at least one of an ACE inhibitor and a ARB combined intoa deliverable form; delivering the composition to an individual'scirculatory system; reducing the level of angiotensin II in theindividual through the action of the dosage of the at least one of theACE inhibitor and the ARB during a period of time; and activating theGABA receptors through the action of the GABA or GABA-a analog duringthe period of time to promote production and release of smooth musclerelaxing substances by the activation of the GABA-a receptors.
 12. Amethod as claimed in claim 11 wherein the step of providing adeliverable form of the composition includes providing the compositionin one of tablets, capsules and IVs.
 13. A method as claimed in claim 11wherein the step of providing a deliverable form of the compositionincludes providing the composition as a tablet including the GABA orGABA-a analog in time release form.
 14. A method as claimed in claim 11wherein the step of providing a deliverable form of the compositionincludes providing the composition as a capsule including the GABA orGABA-a analog in time release form.
 15. A method as claimed in claim 11wherein the GABA or GABA-a analog dose is in the range of 1 mg/day to 10gms/day, and at least one of the ACE-I dose being in the range of 1mg/day to 450 mgs/day and the ARB dose being in the range of 1 mg/day to1000 mg/day.
 16. A method as claimed in claim 11 wherein activating theGABA receptors through the action of the GABA or GABA-a analog duringthe period of time includes delivering the GABA or GABA-a analog in atime release manner.